Genetic Variant AIRE:p.Leu7_Val38del (chr21-44286024-GCTACGCCGGCTTCTGAGGCTGCACCGCACGGAGATCGCGGTGGCCGTGGACAGCGCCTTCCCACTGCTGCACGCGCTGGCTGACCACGACGTGGTC-G) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM4PP5_Moderate

The NM_000383.4(AIRE):c.20_115delTACGCCGGCTTCTGAGGCTGCACCGCACGGAGATCGCGGTGGCCGTGGACAGCGCCTTCCCACTGCTGCACGCGCTGGCTGACCACGACGTGGTCC(p.Leu7_Val38del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L7L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

AIRE
NM_000383.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.28

Variant links:

Genes affected

AIRE (HGNC:360): (autoimmune regulator) This gene encodes a transcriptional regulator that forms nuclear bodies and interacts with the transcriptional coactivator CREB binding protein. The encoded protein plays an important role in immunity by regulating the expression of autoantigens and negative selection of autoreactive T-cells in the thymus. Mutations in this gene cause the rare autosomal-recessive systemic autoimmune disease termed autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy (APECED). [provided by RefSeq, Jun 2012]

AIRE links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000383.4

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_000383.4.

PP5

Variant 21-44286024-GCTACGCCGGCTTCTGAGGCTGCACCGCACGGAGATCGCGGTGGCCGTGGACAGCGCCTTCCCACTGCTGCACGCGCTGGCTGACCACGACGTGGTC-G is Pathogenic according to our data. Variant chr21-44286024-GCTACGCCGGCTTCTGAGGCTGCACCGCACGGAGATCGCGGTGGCCGTGGACAGCGCCTTCCCACTGCTGCACGCGCTGGCTGACCACGACGTGGTC-G is described in ClinVar as [Pathogenic]. Clinvar id is 2580370.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIRE	NM_000383.4 link	c.20_115delTACGCCGGCTTCTGAGGCTGCACCGCACGGAGATCGCGGTGGCCGTGGACAGCGCCTTCCCACTGCTGCACGCGCTGGCTGACCACGACGTGGTCC	p.Leu7_Val38del	disruptive_inframe_deletion	Exon 1 of 14	ENST00000291582.6	NP_000374.1	O43918-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AIRE	ENST00000291582.6 link	c.20_115delTACGCCGGCTTCTGAGGCTGCACCGCACGGAGATCGCGGTGGCCGTGGACAGCGCCTTCCCACTGCTGCACGCGCTGGCTGACCACGACGTGGTCC	p.Leu7_Val38del	disruptive_inframe_deletion	Exon 1 of 14	1	NM_000383.4	ENSP00000291582.5	O43918-1
AIRE	ENST00000527919.5 link	n.181_276delTACGCCGGCTTCTGAGGCTGCACCGCACGGAGATCGCGGTGGCCGTGGACAGCGCCTTCCCACTGCTGCACGCGCTGGCTGACCACGACGTGGTCC		non_coding_transcript_exon_variant	Exon 1 of 14	2
AIRE	ENST00000530812.5 link	n.189_284delTACGCCGGCTTCTGAGGCTGCACCGCACGGAGATCGCGGTGGCCGTGGACAGCGCCTTCCCACTGCTGCACGCGCTGGCTGACCACGACGTGGTCC		non_coding_transcript_exon_variant	Exon 1 of 12	2

Frequencies

GnomAD3 genomes

Cov.:

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Polyglandular autoimmune syndrome, type 1

Pathogenic:1

Sep 14, 2023

National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.